History:

The chemical compound that is currently know as histamine (4-imidazole ethylamine) was first synthesised in 1907.  Subsequent pharmacologic studies of the compound (1910-11) demonstrated that it was active on smooth mucle, producing vasodilatation that resulted in reduced blood pressure.  Additional research indicated that allergic reactions produced symptoms that were very similar to those of poisoning by this compound.  The same chemical compound was isolated by Best, et al., in 1927 from liver and lung tissues.  The presence of the organic amine compound in many other tissues, body-wide, led to its being named histamine (Gr histos, meaning tissue).  It is usually considered one of the local hormones or autocoids.  In the early 1940s, pharmacologic antagonists were synthesised.  These agents blocked the action of histamine at what was identified in the mid-1960s as the H₁ type receptor.  The early 1970s saw the discovery of the H₂ receptor and the emergence of antagonists to it.  Additionally, a decade later a third H₃ receptor was identified.  The function of this third histaminergic receptor has not been fully elucidated.  However, its predominance on pre-synaptic neurones implies a role as an autoreceptor.

Histamine is widely distributed throughout most tissues and is also present in many venoms, bacteria, and plants.  The synthetic and metabolic pathways of histamine are as follows:

Following synthesis, histamine is stored in mast cells of the nose, mouth, feet, and internal body surfaces and basophils of the blood.  Turnover of histamine in these cells is relatively slow and, if depleted, may take weeks to return to normal levels.  Histamine is also found in cells of the skin, enterochromaffin-like cells of the gastric mucosa, and neurones of the central and peripheral nervous system.  Histamine in these areas exhibits a relatively rapid turnover rate.

Release of Histamine in Allergic/Immune Reactions

In addition to histamine, various other compounds are released that contribute to the inflammatory response, including platelet activating factor (PAF) and metabolites of arachidonic acid such as leukotrienes (LKTs) and prostaglandins (PGs) as well as other cytokines, tumour necrosis factor (TNF) and inflammatory mediators.

NOTE: Histamine may exhibit a negative feedback effect on basophils and mast cells in skin BUT NOT in the lung.

Organic Bases -- many basic organic compounds may either displace or cause the release of histamine, including amides, quaternary ammonium compounds, alkaloids such as morphine and tubocurarine, radiocontrast media, basic antibiotics such as vancomycin ("red-man" syndrome), and carbohydrate plasma expanders.  Additionally, endogenous substances such as bradykinin and Substance P may cause the release of histamine without prior sensitisation.  All of these promptors involve increases in intracellular calcium either by ionophoresis (opening of channels) or release of internal stores of calcium.  Some compounds, such as the wasp venom mastoparan, may release histamine by activating a G protein coupled phospholipase C cascade event.

 Mechanical/Chemical Injury -- cellular injury due to mechanical injury (i.e. scratches), radiation (sunburn), or chemical injury (organic solvents) may cause the release of histamine without the typical immune response described above.

 Histamine release in the stomach is mediated by gastrin and vagal stimulation leading to release of acetylcholine, both of which have receptors on the enterochromaffin-like mast cells that contain histamine.  Occupation of the gastrin or cholinergic muscarinic receptor will cause the exocytosis of granules and subsequent histamine release.

 Histamine release from histaminergic neurones is similar to the release of other neurotransmitter substances.

Three receptors specific for histamine have been identified.  All are typical 7-transmembrane proteins coupled to G proteins that act as second messengers.


 

Receptor:	G Protein:	Second Messenger:	Location:
H1	Gq/11	PI/DAG	Smooth muscle, endothelium, brain
H2	Gs	AC/cAMP	gastric mucosa, smooth muscle, cardiac muscle, brain
H3	G?	Unknown	Pre-synaptic brain, peripheral nerves

Vasculature
Capillary
H₁ - Vasodilatation -- rapid onset short duration of action --   Histamine acts at receptors on the endothelium and the effect is mediated by the prostaglandin prostacycline (PGI₂)
H₂  - Vasodilatation -- slower OOA and sustained DOA -- Histamine acts on receptors on the smooth muscle and the mechanism of dilatation is presumed to be similar to that of beta adrenergic dilatation, cAMP mediated.


Post-capillary venules -- Histamine results in increased permeability of these vessels, leading to the development of local œdema.
 

The responses described above contribute to the "Triple Response" of histamine injection.
Red spot -- a bright red spot a few millimetres in diametre around the initial  site  of injection, due to the immediate vasodilatation.

Flare -- a less intense red area extending approximately 1 cm beyond the site, due to local distribution of the histamine and neuronal-mediated dilatation.

Wheal -- œdema that develops one to two minutes post-injection at the injection  site, due to the increase in permeability.
 

Large Vessels -- Vasoconstriction.  The exact mechanism of histamine-induced vasoconstriction is not know.  The effect is species dependent, with rodents exhibiting profound vasoconstriction while in humans the effect is relatively minor and practicably negligible due to the predominance of intense small vessel vasodilatation.
 
Heart -- Histamine exerts the following effects on the heart:
Positive inotropy -- in both the atria and ventricles, due to H₂ mediated increases in calcium permeability.

Positive chronotropy -- due to H₂ mediated early diastolic depolarisation in the SA node. Increased Automaticity which may lead to arrhythmias.

Decreased AV nodal conduction -- mediated by H₁ receptors.
 

Extravascular Smooth Muscle -- H₁ receptor occupation by histamine will result in smooth muscle contraction.  H₂  receptor occupation will result in relaxation.  Histamine induced smooth muscle contraction predominates, presumably due to a higher affinity for and greater number of H₁ receptors.  These actions mediate the following effects:
Gastrointestinal Tract -- diarrhoea
Bronchus -- bronchospasm
NOTE that histamine-induced bronchspasm is exceedingly   more profound in patients with asthma, as compared to non-asthmatics.
Other Smooth Muscle Effects are negligible in humans.
Exocrine Glands -- Histamine has little effect on most exocrine glands with the following exceptions:
Gastric glands -- Histamine is one of the primary mediators of gastric acid secretion.  Activation of H₂  receptors will increase acid, pepsin, and intrinsic factor secretion from these glands.
 
Adrenal medulla -- At extremely high doses of histamine, an increase in the secretion of adrenaline from the adrenal medulla will occur.
 
Peripheral Nerves -- Histamine activates those peripheral nerves that correspond to itch (epidermis) and pain (dermis and epidermis) and also fire those neurones that mediate vascular dilatation.  All of these effects are mediated by the H₁ receptor.
 
Central Nervous System -- H₁ receptor activation within the CNS will increase wakefullness and depress appetite.  Both H₁ and H₂  receptors play a role in the central control of thirst, body temperature, blood pressure, pain perception, and the release of anti-diuretic hormone (ADH).
 
Clinical Uses of Histamine:
 1) Pulmonary Function Test in Asthmatics -- small, controlled doses of histamine may be administered via nebuliser to test bronchial hypersensitivity.  The degree of reactivity of the bronchus to varying doses of histamine correlates to the severity of asthma in the patient.  These tests MUST be well controlled in case of massive reactivity and total bronchial obstruction.
 
 2) Histamine is also used as a positive control in skin allergy testing.